IMIDAZOPYRIMIDINES AS EED INHIBITORS AND THE USE THEREOF

1 . A compound of Formula I:

wherein:

R 1 is aralkyl;

R 2 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;

R 3 and R 4 taken together with the carbon atoms to which they are attached form a radical of Formula I-A, I-B, or I-C:

X is selected from the group consisting of —C(R 5a )(R 5b )—, —C(═O)—, and —S(═O) 2 —;

R 5a and R 5b are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;

Y is selected from the group consisting of —C(R 6a )(R 6b )—, —S—, —O—, and —N(R 7 )—; or

X and Y taken together form a 5-membered heteroarylenyl;

Z is —C(R 6c )(R 6d ) m —;

R 6a and R 6b are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;

each R 6c and R 6d is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;

m is 0, 1, or 2;

R 7 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, optionally substituted C 3 —C cycloalkyl, optionally substituted C 4 -C 8 heterocyclo, hydroxyalkyl, (alkoxy)alkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl;

R 8a , R 8b , and R 8c are independently selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, carboxamido, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, (heterocyclo)C 1 -C 4 alkyl, and alkylsulfonyl;

 is a fused phenyl, fused 5-membered heteroaryl, or fused 6-membered heteroaryl;

 is an optionally substituted fused 3- to 8-membered cycloalkyl or optionally substituted fused 4- to 8-membered heterocyclo;

 is an optionally substituted fused 4- to 8-membered heterocyclo;

the bond designated with a “ ” is attached at the R 3 position of Formula I and the bond designated with an “*” is attached at the R 4 position of Formula I; or

R 3 is R 3a ;

R 4 is R 4a ;

R 3a is selected from group consisting of optionally substituted aryl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 4- to 8-membered heterocyclo; and

R 4a is selected from the group consisting of hydrogen, halo, C 1 -C 4 haloalkyl, —S(═O) 2 R 9 , —P(═O)(R 10a )(R 10b ), —C(═O)OR 11a , —C(═O)NR 11b R 11c and —S(═O)(=NR 13a )R 13b ;

R 9 is selected from the group consisting of C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl;

R 10a and R 10b are independently C 1 -C 4 alkyl;

R 11a is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;

R 11b and R 11c are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; or

R 11b and R 11c taken together with the nitrogen atom to which they are attached form a 4- to 6-membered optionally substituted heterocyclo;

R 13a is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and hydroxyalkyl;

R 13b is selected from the group consisting of C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl; or

R 13a and R 13b taken together form a 5- to 7-membered heterocyclo; and

is a single or double bond,

or a pharmaceutically acceptable salt or solvate thereof.

2 . The compound of claim 1 of Formula II:

or a pharmaceutically acceptable salt or solvate thereof.

3 . The compound of claim 2 of Formula III:

wherein L is selected from the group consisting of —C(R 8b )═ and —N=, or a pharmaceutically acceptable salt or solvate thereof.

4 . The compound of claim 3 of Formula IV:

wherein L is selected from the group consisting of —C(R 8b )═ and —N=, or a pharmaceutically acceptable salt or solvate thereof.

5 . The compound of claim 1 , wherein Z is —CH 2 —, or a pharmaceutically acceptable salt or solvate thereof.

6 . The compound of claim 1 , wherein:

X is selected from the group consisting of —C(R 5a )(R 5b )—, —C(═O)—, and —S(═O) 2 —; and

Y is selected from the group consisting of —C(R 6a )(R 6b )—, —S—, —O—, and —N(R 7 )—, or a pharmaceutically acceptable salt or solvate thereof.

7 . The compound of claim 1 , wherein X is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

8 . The compound of claim 1 , wherein Y is —N(R 7 )—, or a pharmaceutically acceptable salt or solvate thereof.

9 . The compound of claim 1 , wherein X and Y taken together form a 5-membered heteroarylenyl, or a pharmaceutically acceptable salt or solvate thereof.

10 . The compound of claim 1 of Formula XVI:

or a pharmaceutically acceptable salt or solvate thereof.

11 . The compound of claim 1 , wherein:

R 1 is R 1 -1:

R 12a , R 12b , and R 12c are each independently selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;

W is selected from the group consisting of —CH 2 — and —C(═O)—; and

t is 1 or 2,

or a pharmaceutically acceptable salt or solvate thereof.

12 . The compound of claim 11 , wherein:

R 12a is fluoro; and

R 12b and R 12c are independently selected from the group consisting of hydrogen and fluoro,

or a pharmaceutically acceptable salt or solvate thereof.

13 . The compound of claim 1 selected from any one or more of the compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

14 . The compound of claim 13 selected from group consisting of:

4-ethyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one;

12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one;

4-cyclopropyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one;

12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one; and

11-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-methyl-4H-3-thia-2,5,10,11a-tetraazadibenzo[cd,f]azulene 3,3-dioxide,

or a pharmaceutically acceptable salt or solvate thereof.

15 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

16 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof.

17 . The method of claim 16 , wherein the cancer is any one or more of the cancers of Table 3.

18 . A compound of Formula XVII:

wherein:

R 1 is aralkyl;

R 2 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;

R 7 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, optionally substituted C 3 —C cycloalkyl, optionally substituted C 4 -C 8 heterocyclo, hydroxyalkyl, (alkoxy)alkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl;

R 8a , R 8b , and R 8c are independently selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and alkylsulfonyl;

 is phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; and

is a single or double bond,

or a pharmaceutically acceptable salt or solvate thereof.

19 . A compound of Formula XVIII:

wherein:

R 1 is aralkyl;

R 2 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;

R 7 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, optionally substituted C 3 —C cycloalkyl, optionally substituted C 4 -C 8 heterocyclo, hydroxyalkyl, (alkoxy)alkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl;

 is optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 4- to 8-membered heterocyclo; and

is a single or double bond,

or a pharmaceutically acceptable salt or solvate thereof.

20 . A compound of Formula XIX:

wherein:

R 1 is aralkyl;

R 2 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;

R 7 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, optionally substituted C 3 —C cycloalkyl, optionally substituted C 4 -C 8 heterocyclo, hydroxyalkyl, (alkoxy)alkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl; and

 is optionally substituted 4- to 8-membered heterocyclo,

or a pharmaceutically acceptable salt or solvate thereof.